1. Field of the Invention
The present invention relates generally to the field of medical therapy of renal disease. More specifically, the present invention relates to the use of trisodium citrate-containing dialysate solutions during hemodialysis and continuous renal replacement therapy, wherein trisodium citrate functions as a regional anticoagulant.
2. Description of the Related Art
Continuous arteriovenous hemodialysis (CAVHD) and other forms of continuous renal replacement therapy (CRRT) are being used increasingly as the major form of renal replacement therapy for critically ill patients with acute renal failure (ARF). Generally, the procedure has required systemic anticoagulation utilizing heparin or, in a few cases, prostacyclin to maintain filter patency. Although heparin is removed by continuous arteriovenous hemodialysis membranes, systemic anticoagulation is usually unavoidable with heparin and has been associated with an increased incidence of bleeding. In order to circumvent this problem, regional heparin anticoagulation has been tried, but this has not gained widespread acceptance due to the difficulty in accurately adjusting protamine doses. Similarly, continuous arteriovenous hemodialysis has been attempted with frequent saline flushes through the filter, but it has been difficult to keep the filter patent for longer than 24 hours.
U.S. Pat. No. 5,032,615 describes a technique employing sodium citrate as a regional anticoagulant for continuous arteriovenous hemodialysis (citrate CAVHD) which results in removal of excess water, electrolytes and catabolic toxins without requiring systemic anticoagulation. Citrate is infused at the origin of the extracorporeal circuit, and the citrate-calcium chelate is removed by diffusion across the membrane. The metabolic consequences of the sodium citrate load are compensated for by the use of a special dialysate containing no alkali, subnormal sodium concentration, and no calcium. Calcium homeostasis is restored by a peripheral infusion of calcium chloride into the patient.
Trisodium citrate (TSC) chelates calcium and thereby acts as a regional anticoagulant of extra-corporal circuits. Available from two different commercial vendors (as 4% and 46.7% solutions in sterile water), trisodium citrate is indicated and FDA approved as an anticoagulant for extra-corporal blood fractionation and cytopharesis. Direct intravenous infusion of this product is contraindicated, and in the case of 46.7% TSC can be exceedingly dangerous.
However, recent experience in critical care units has demonstrated that intravenously administered trisodium citrate is effective as an extra-corporal anticoagulant during various forms of acute dialysis, including continuous modes of hemofiltration and dialysis (1-5). With careful management of the ionized calcium and the rate of citrate infusion, it is possible to provide effective regional anticoagulation of the extra-corporal circuit without any adverse effects on the systemic clotting parameters (as assessed by Prothrombin Times (PT) and Partial Thromboplastin Times (PTT)).
The toxicities of this approach include metabolic alkalosis due to citrate accumulation and its subsequent metabolism to bicarbonate, and the effects of reduced systemic ionized calcium. Subjectively the patient may experience palpitations, perioral tingling and stomach cramps. Objective features of citrate toxicity include myocardial depression, arrhythmias and systemic alkalosis which may or may not include an anion gap. Proper surveillance of the rate of citrate administration and monitoring and correction of systemic ionized calcium may obviate these effects. Patients with severe liver disease may be prone to developing citrate toxicity and caution must be exercised in treating these patients with citrate (6). The recent clinical experience at the University of Alabama at Birmingham has demonstrated that 2% TSC infused in the prefilter circuit at 17.5 to 24.5 mmol citrate/hour, with dialysis against a normal saline dialysate solution (also containing 3 mM KCl, and 1 mM MgSO4) provides safe and effective regional anticoagulation for continuous renal replacement therapy. The 2% TSC solution is isotonic and avoids problems with hypernatremia as has been observed with 4% TSC solutions. Furthermore, an isotonic saline dialysis solution (free of any buffer) is used at 1000 ml/hour which simplifies the preparation of the required solutions and minimizes administration errors. Infusion of 2% TSC in the prefilter circuit at 250 to 350 ml/hour (17.5 to 24.5 mmoles citrate/hour) provides adequate buffer input to maintain systemic acid-base balance, and results in effective calcium chelation of the extracorporal circuit with post-filter ionized calcium levels generally between 0.4 and 0.5 mM. Systemic ionized calcium is corrected to 1.0 to 1.1 mM by central infusion of calcium gluconate. This simplified approach to citrate regional anticoagulation has proven to be safe and effective and is now the standard of care for continuous renal replacement therapy in the intensive care units at the University of Alabama at Birmingham (7).
Heparin is the traditional anticoagulant used during hemodialysis procedures, but its use is accompanied with a number of serious side effects, including systemic anticoagulation, thrombocytopenia and suppressed aldosterone secretion. The effects on systemic coagulation make heparin administration very problematic in patients with gastrointestinal bleeding or traumatic injury in which hemostasis is impaired due to coagulation factor consumption or occult bleeding from wounds or vascular puncture sites. Furthermore, a number of patients are hyper-coagulable and even with maximal heparin administration, there is still clotting and loss of the extra-corporal dialysis circuit.
xe2x80x9cNo heparinxe2x80x9d dialysis is possible but this requires frequent saline flushes of the extra-corporal circuit which is generally ineffective in the artificial kidney which is composed of a myriad of parallel minute fibers. Clotting of the circuit requires replacement of the entire circuit with attendant expense, inconvenience and loss of clinical efficacy. Recently, Ahmad et al. (8) described citric acid in dialysis solutions. Citric acid was used to prepare a xe2x80x9cdry dialysatexe2x80x9d for chronic dialysis. When reconstituted with water, the citric acid titrates bicarbonate to set the pH. Ionized Calcium was not monitored and chelation of Calcium resulted in anticoagulation was not considered.
While the use of trisodium citrate is approved for addition to whole blood in an extra-corporal circuit, the indication is for fraction of blood products and for cytopharesis. As such, the intravenous administration of trisodium citrate as a regional anticoagulant for hemo-dialysis represents an xe2x80x9coff-labelxe2x80x9d use of this FDA-approved agent.
The prior art is deficient in a protocol presenting a mechanism whereby trisodium citrate can be used as a regional anticoagulant during hemodialysis and continuous renal replacement therapy by including it in the dialysate fluid, and thereby avoiding direct intravenous administration. The present invention fulfills this long-standing need and desire in the art.
The present invention is directed to a new dialysate solution which contains trisodium citrate, wherein trisodium citrate functions as a regional anticoagulant for dialysis treatment. This dialysate would not be administered intravenously. Diffusive flux of citrate across the dialysis membranes would provide base equivalents to the patient and would also chelate calcium in the extracorporal circuit. The major advantages of this approach is that it would be compatible with the current continuous renal replacement therapy (CRRT) devices in clinical use and could be readily adapted to acute intermittent hemodialysis.
In one embodiment of the present invention, there is provided a dialysate containing trisodium citrate.
In another embodiment of the present invention, there is provided a method of treating an individual having a renal disease by applying acute hemodialysis to the individual using the dialysate disclosed herein, wherein the dialysate is administered via dialysis circuits.
In still another embodiment of the present invention, there is provided a method of treating an individual having a renal disease by applying continuous renal replacement therapy to the individual using the dialysate disclosed herein, wherein the dialysate is administered via dialysis circuits.
In yet another embodiment of the present invention, there is provided a method of providing regional anticoagulation during acute hemodialysis in an individual in need of such treatment by administering the dialysate disclosed herein to the individual via dialysis circuits.
In still yet another embodiment of the present invention, there is provided a method of providing regional anticoagulation during continuous renal replacement therapy in an individual in need of such treatment by administering the dialysate disclosed herein to the individual via dialysis circuits.
Additional applications of the dialysate disclosed herein include correction of severe systemic metabolic alkalosis by greatly reducing the citrate delivery rate in the dialysis solution, and correction of severe systemic metabolic acidosis by greatly increasing the citrate delivery rate in the dialysis solution. In either instance, parallel infusion of calcium gluconate or calcium chloride into the central systemic circulation with careful monitoring of the systemic ionized calcium will prevent inordinant excursions of the systemic ionized calcium level. Such applications are applicable in both the acute intermittent hemodialysis and continuous renal replacement therapy settings.
Other and further aspects, features, and advantages of the present invention will be apparent from the following description of the presently preferred embodiments of the invention. These embodiments are given for the purpose of disclosure.